11a-Homo-PG intermediates for preparing 11a-methano TXA2 compounds

ABSTRACT

The present invention provides novel thromboxane analogs and intermediates. Particularly, the present invention provides novel 11a-homo-PG intermediates for preparing 11a-methano TXA 2  compounds.

CROSS REFERENCE TO RELATED APPLICATION

The present application is a division of Ser. No. 035,143, filed May 1, 1979 now U.S. Pat. No. 4,218,378.

BACKGROUND OF THE INVENTION

The present invention provides novel thromboxane analogs and intermediates. Particularly, the present invention provides novel 11a-homo-PG intermediates for preparing 11a-methano TXA₂ compounds. The essential material constituting a disclosure of the preparation and use of the compounds described above is incorporated here by reference from the U.S. Ser. No. 035,143 now U.S. Pat. No. 4,128,378.

PRIOR ART

Known in the art are the cyclohexane analogs of PGF₂α and PGE₂, e.g., 10a-homo-PGF₂α and 10a-homo-PGE₂. See Crossley, N. S., Tett. Lett. 36:3327-3330 (1971). Also racemic 11a-homo-PGE₁ is described by Floyd, M. B., et al., J. Org. Chem. 44:71-75 (1979). A related cyclohexene is describewd by Muchowski, J. M., et al., Prostaglandins 75:297-302 (1975) and certain 11-deoxy-11a-homo PG's are described in Derwent Farmdoc CPI 29086Y, abstracting French Pat. No. 2,327,768.

SUMMARY OF THE INVENTION

The present invention particularly provides a thromboxane intermediate of formula V, VI, VII, VIII, IX, or X, ##STR1##

wherein M₇ is α-R₅ :β-OR₁₀, α-OR₁₀ :β-R₅, or α-H:β-H, wherein R₁₀ is a stable, acid hydrolyzable blocking group;

wherein R₁₂ is alkyl of one to 12 carbon atoms, inclusive, aralkyl of 7 to 12 carbon atoms, inclusive; phenyl; or phenyl substituted with one, two, or three chloro or alkyl of one to 3 carbon atoms;

wherein Y₁ is

(1) trans--CH═CH--,

(2) cis--CH═CH--,

(3) --CH₂ CH₂ --, or

(4) --C.tbd.C--,

wherein M₁ is α-R₅ :β-OH, α-OH:β-R₅, or α-H:β-H, wherein R₅ is hydrogen or methyl, and wherein L₁ is α-R₃ :β-R₄, α-R₄ :β-R₃, or a mixture of α-R₃ :β-R₄ and β-R₃ :α-R₄, wherein R₃ and R₄ are hydrogen, methyl, or fluoro, being the same or different, with the proviso that one of R₃ and R₄ is fluoro only when the other is hydrogen or fluoro, or wherein -C(M₁)-C(L₁)- is trans--CH═CH--;

wherein Z₁ is

(1) cis--CH═CH--CH₂ --(CH₂)_(g) --CH₂ --,

(2) cis--CH═CH--CH₂ --(CH₂)_(g) --CF₂ --, (3) cis--CH₂ --CH═CH--(CH₂)_(g) --CH₂ --,

(4) --(CH₂)₃ --(CH₂)_(g) --CH₂ --,

(5) --(CH₂)₃ --(CH₂)_(g) --CF₂ --,

(6) --CH₂ --O--CH₂ --(CH₂)_(g) --CH₂ --,

(7) --(CH₂)₂ --O--(CH₂)_(g) --CH₂ --, or

(8) trans--CH₂ --(CH₂)_(g) --CH₂ -CH═CH-;

(9) --(m-Ph)--O--(CH₂)_(g) --, or

(10) --(m-Ph)--CH₂ --(CH₂)_(g) --,

wherein g is one, 2, or 3 and -(m-Ph)- is meta-phenylene; and

wherein R₇ is

(1) -(CH₂)_(m) -CH₃, wherein m is an integer from one to 5, inclusive;

(2) phenoxy;

(3) phenoxy substituted by one, two or three chloro, fluoro, trifluoromethyl, alkyl of one to 3 carbon atoms, inclusive, or alkoxy of one to 3 carbon atoms, inclusive, with the proviso that not more than two substituents are other than alkyl;

(4) phenyl;

(5) phenyl substituted by one, two or three chloro, fluoro, trifluoromethyl, alkyl of one to 3 carbon atoms, inclusive, or alkoxy of one to 3 carbon atoms, inclusive, with the proviso that not more than two substituents are other than alkyl;

(6) phenylmethyl, phenylethyl, or phenylpropyl;

or

(7) phenylmethyl, phenylethyl, or phenylpropyl substituted by one, two or three chloro, fluoro, trifluoromethyl, alkyl of one to 3 carbon atoms, inclusive, or alkoxy of one to 3 carbon atoms, inclusive, with the proviso that not more than two substituents are other than alkyl; with the proviso that R₇ is phenoxy or substituted phenoxy, only when R₃ and R₄ are hydrogen or methyl, being the same or different.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The novel 11a-methano-TXA analogs of the present invention are all highly active as inhibitors of thromboxane synthetase and accordingly are useful for anti-inflammatory, anti-asthma, and anti-thrombotic indications. 

I claim:
 1. A thromboxane intermediate of formula V, VI, VII or VIII, ##STR2## wherein M₇ is α-R₅ :β-OR₁₀, α-OR₁₀ :βR₅, or α-H:β-H, wherein R₅ is hydrogen or methyl and R₁₀ is a stable, acid hydrolyzable blocking group;wherein R₁₂ is alkyl of one to 12 carbon atoms, inclusive, aralkyl of 7 to 12 carbon atoms, inclusive; phenyl; or phenyl substituted with one, two, or three chloro or alkyl of one to 3 carbon atoms; wherein Y₁ is(1) trans--CH═CH--, (2) cis--CH═CH--, (3) --CH₂ CH₂ --, or (4) --C.tbd.C--, wherein L₁ is α-R₃ :β-R₄, α-R₄ :β-R₃, or a mixture of α-R₃ :β-R₄ and β-R₃ :α-R₄, wherein R₃ and R₄ are hydrogen, methyl, or fluoro, being the same or different, with the proviso that one of R₃ and R₄ is fluoro only when the other is hydrogen or fluoro, wherein Z₁ is(1) cis--CH═CH--CH₂ --(CH₂)_(g) --CH₂ --, (2) cis--CH═CH--CH₂ --(CH₂)_(g) --CF₂ --,(3) cis--CH₂ --CH═CH--(CH₂)_(g) --CH₂ --, (4) --(CH₂)₃ --(CH₂)_(g) --CH₂ --, (5) --(CH₂)₃ --(CH₂)_(g) --CF₂ --, (6) --CH₂ --O--CH₂ --(CH₂)_(g) --CH₂ --, (7) --(CH₂)₂ --O--(CH₂)_(g) --CH₂ --, or (8) trans--CH₂ --(CH₂)_(g) --CH₂ --CH═CH--; (9) --(m-Ph)--O--(CH₂)_(g) --, or (10) --(m-Ph)--CH₂ --(CH₂)_(g) --,wherein g is one, 2, or 3 and -(m-Ph)- is meta-phenylene; and wherein R₇ is(1) -(CH₂)_(m) -CH₃, wherein m is an integer from one to 5, inclusive; (2) phenoxy; (3) phenoxy substituted by one, two or three chloro, fluoro, trifluoromethyl, alkyl of one to 3 carbon atoms, inclusive, or alkoxy of one to 3 carbon atoms, inclusive, with the proviso that not more than two substituents are other than alkyl; (4) phenyl; (5) phenyl substituted by one, two or three chloro, fluoro, trifluoromethyl, alkyl of one to 3 carbon atoms, inclusive, or alkoxy of one to 3 carbon atoms, inclusive, with the proviso that not more than two substituents are other than alkyl; (6) phenylmethyl, phenylethyl, or phenylpropyl; or (7) phenylmethyl, phenylethyl, or phenylpropyl substituted by one, two or three chloro, fluoro, trifluoromethyl, alkyl of one to 3 carbon atoms, inclusive, or alkoxy of one to 3 carbon atoms, inclusive, with the proviso that not more than two substituents are other than alkyl; with the proviso that R₇ is phenoxy or substituted phenoxy, only when R₃ and R₄ are hydrogen or methyl, being the same or different. 